Journal of Alzheimer's Disease - Volume 101, issue 4

Authors: Veronelli, Laura | Daini, Roberta | Mannino, Alice | Rossetti, Alessia | Gilardone, Giulia | Corbo, Massimo | Primativo, Silvia

Article Type: Research Article

Abstract: Background: Visuo-perceptual and visuo-attentional disorders, such as global processing deficit and simultanagnosia, are not routinely investigated in prodromal forms of typical Alzheimer’s disease, as amnestic mild cognitive impairment (MCI). Objective: This study evaluated global processing abilities through Navon’s classical paradigm in individuals with amnestic MCI and investigated the related visuo-perceptual and attentional components involved in simultanagnosia. Methods: Sixteen consecutive patients with amnestic MCI (6 single-domain, 10 multiple-domain) and 16 matched controls were requested to identify global and local elements of hierarchical Navon letters, and to name large and small solid letters. Results: While correctly …identifying solid letters, patients with multiple-domain amnestic MCI were less accurate in processing the global level of hierarchical stimuli compared to controls. Single-case analyses suggested that global processing may also be impaired in single-domain amnestic MCI. In addition, patients with pathological performance in the Navon task showed perceptual and/or visual focal attention deficits. Conclusions: Early dysfunction of holistic processing can be detected in amnestic MCI. Visuo-perceptual and/or visual focal attention mechanisms, which have been shown to be damaged in Posterior Cortical Atrophy patients with simultanagnosia, may be impaired in individuals with amnestic MCI. Investigation and identification of global processing deficits in MCI could contribute to early diagnosis and longitudinal monitoring of the disease. Show more

Keywords: Alzheimer’s disease, focal attention, global processing deficits, mild cognitive impairment, Navon, simultanagnosia, visuo-perceptual processing

DOI: 10.3233/JAD-240375

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1151-1165, 2024

Authors: Chan, Carol K. | Lane, Kathleen A. | Gao, Sujuan | Adeoye-Olatunde, Omolola A. | Biber, Sarah | Glover, Crystal M. | Johnson, David K. | Risacher, Shannon L. | Saykin, Andrew J. | Wang, Sophia

Article Type: Research Article

Abstract: Background: Despite the need to increase engagement of underrepresented groups (URG) in Alzheimer’s disease and related dementias (ADRD) studies, enrollment remains low. Objective: Compare referral sources across racial and ethnic groups among participants enrolled in ADRC studies. Methods: Data for this cross-sectional secondary analysis were extracted from the National Alzheimer’s Coordinating Center Uniform Data Set. We performed mixed effects logistic regression models using generalized estimating equations for professional referral versus non-professional referral by racial and ethnic group, adjusted for age, gender, education, visit year, and Clinical Dementia Rating scale (CDR) with a random effect for study …site. Results: Included in the analysis were 48,330 participants across 46 ADRCs (mean [SD] age, 71.3 [10.5] years; 20,767 female [57%]; 4,138 Hispanic [8.6%]; 1,392 non-Hispanic Asian [2.9%]; 6,766 non-Hispanic Black [14%] individuals; and 676 individuals [1.4%] of other races. Non-Hispanic Black and Asian participants had lower odds of being referred by a professional contact compared to non-Hispanic White participants (Black: adjusted OR = 0.61, 95% CI = 0.44–0.86, p  = 0.005; Asian: adjusted OR = 0.65, 95% CI, p  = 0.004). In participants who had completed an MRI, there was no significant difference in referral source across ethnic and racial groups. Conclusions: Further studies are needed to better understand the systemic and structural factors that contribute to differences in referral sources and disparities in recruitment of URG into ADRD studies. Show more

Keywords: Alzheimer’s disease, diversity, language, race and ethnicity, recruitment

DOI: 10.3233/JAD-240485

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1167-1176, 2024

Authors: Abi-Ghanem, Charly | Salinero, Abigail E. | Smith, Rachel M. | Kelly, Richard D. | Belanger, Kasey M. | Richard, Riane N. | Paul, Aaron S. | Herzog, Ava A. | Thrasher, Christina A. | Rybka, Krystyna A. | Riccio, David | Gannon, Olivia J. | Kordit, David | Kyaw, Nyi-Rein | Mansour, Febronia M. | Groom, Emily | Brooks, Heddwen L. | Robison, Lisa S. | Pumiglia, Kevin | Zuloaga, Damian G. | Zuloaga, Kristen L.

Article Type: Research Article

Abstract: Background: About two-thirds of those with Alzheimer’s disease (AD) are women, most of whom are post-menopausal. Menopause accelerates dementia risk by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid-life metabolic disease (obesity, diabetes/prediabetes) is a well-known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents. Objective: Our goal was to determine the effects of a high fat diet on metabolic outcomes in the AppNL-F knock-in mouse model of AD and assess the effects of menopause. Methods: First, 3-month-old AppNL-F and WT female …mice were placed on either a control or a high fat diet until 10 months of age then assessed for metabolic outcomes. Next, we did a more extensive assessment in AppNL-F mice that were administered VCD (4-vinylcyclohexene diepoxide) or vehicle (oil) and placed on a control or high fat diet for 7 months. VCD was used to model menopause by causing accelerated ovarian failure. Results: Compared to WT controls, AD female mice had worse glucose intolerance. Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. There were interactions between diet and menopause on some metabolic health serum biomarkers and the expression of hypothalamic markers related to energy balance. Conclusions: This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD. Show more

Keywords: Alzheimer’s disease, glucose metabolism, hypothalamus, menopause, metabolic disease, obesity

DOI: 10.3233/JAD-231332

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1177-1194, 2024

Authors: Curiel Cid, Rosie E. | Ortega, Alexandra | Vaillancourt, David | Asken, Breton | Crocco, Elizabeth A. | Armstrong, Melissa J. | Duara, Ranjan | Crenshaw, Kirsten | Adjouadi, Malek | Rosselli, Monica | Wang, Wei-en | Loewenstein, David A.

Article Type: Research Article

Abstract: Background: Semantic intrusion errors (SIEs) are both sensitive and specific to PET amyloid-β (Aβ) burden in older adults with amnestic mild cognitive impairment (aMCI). Objective: Plasma Aβ biomarkers including the Aβ42/40 ratio using mass spectrometry are expected to become increasingly valuable in clinical settings. Plasma biomarkers are more clinically informative if linked to cognitive deficits that are salient to Alzheimer’s disease (AD). Methods: This study included 119 older adults enrolled in the 1Florida Alzheimer’s Disease Research Center (ADRC), 45 aMCI participants scored below the established Aβ42/40 ratio cut-off of 0.160 using the Quest AD-Detect™ …assay indicating Aβ positivity (Aβ+), while 50 aMCI participants scored above this cut-off indicating Aβ negative status (Aβ–). Additionally, 24 cognitively unimpaired (CU) persons scored above the cut-off of 0.160 (Aβ–). Results: The aMCI plasma Aβ+ group evidenced the greatest percentage of SIEs, followed by the aMCI Aβ–. The CU Aβ– group exhibited the lowest percentage of SIEs. After adjustment for global cognitive impairment, aMCI plasma Aβ+ continued to demonstrate greater SIEs on tests tapping the failure to recover from proactive semantic interference (frPSI) as compared to the aMCI Aβ–group. Using pre-established cut-offs for frPSI impairment, 8.3% of CU Aβ– participants evidenced deficits, compared to 37.8% of aMCI Aβ–, and 74.0% of aMCI Aβ+. Conclusions: SIEs reflecting frPSI were associated with aMCI Aβ+ status based on the Aβ42/40 ratio. Results suggest the importance of SIEs as salient cognitive markers that map onto underlying AD pathology in the blood. Show more

Keywords: Alzheimer’s disease, amyloid-β, Aβ42/40, LASSI-L, mild cognitive impairment, plasma biomarkers, semantic intrusion errors

DOI: 10.3233/JAD-240164

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1195-1204, 2024

Authors: Lingenberg, Alma | Herrmann, François R. | Armand, Stéphane | Péron, Julie | Assal, Frédéric | Allali, Gilles

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) can present with both episodic amnestic syndrome and biomarkers of Alzheimer’s disease (AD) pathology. Objective: To examine the associations between amnestic syndrome and cerebrospinal fluid (CSF) AD biomarkers in iNPH and the CSF tap test response in iNPH patients with amnestic syndrome. Methods: We used the Free and Cued Selective Reminding Test to divide iNPH into amnestic and non-amnestic patients. We compared their clinical, biological, and radiological characteristics and examined the reversibility of gait spatiotemporal parameters and neuropsychological performances after a CSF tap test. Univariate and multiple linear regression models …examined the association between memory performance and clinical-biological characteristics. Results: Sixty-two non-amnestic patients (mean age 77.0±7.0 years, 38.7% female) and thirty-eight amnestic patients (mean age 77.0±5.9 years, 36.8% female) presented similar levels of AD biomarkers and clinical-radiological profiles. Global cognition and education levels were lower in the amnestic iNPH group. We found no association between AD biomarkers and memory performances (total tau: β= –4.50; 95% CI [–11.96;2.96]; p  = 0.236; amyloid-β (1–42): β= 8.60, 95% CI [–6.30;23.50]; p  = 0.240). At baseline, amnestic iNPH patients performed worse on executive functions, attention, and gait speed but improved similarly to the non-amnestic iNPH patients after the tap test. Conclusions: In our clinical sample of iNPH patients, we confirm the lack of specificity of the amnestic profile for predicting AD pathology. Clinicians should not preclude amnestic iNPH patients from undergoing an invasive procedure of CSF derivation. Show more

Keywords: Alzheimer’s disease, amyloid protein, cerebrospinal fluid biomarkers, diagnosis, episodic memory, idiopathic normal pressure hydrocephalus, memory deficits, neuropsychology, normal pressure hydrocephalus, tau protein

DOI: 10.3233/JAD-240439

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1205-1216, 2024

Authors: Zhang, Tan | Wang, Xin | Jester, Hannah M. | Zhou, Xueyan | Ma, Tao

Article Type: Research Article

Abstract: Background: Apathy is a state of decreased interest, lack of initiative, reduced goal-directed activity and blunted emotional responses. Apathy is one of the most common neuropsychiatric symptoms (NPS) in patients with Alzheimer’s disease (AD) and is also relatively omnipresent in individuals with Down syndrome (DS). Little is known about the apathy-like behaviors in rodent models of AD and DS. Objective: This study aimed to characterize apathy-like behaviors with aging in two established DS mouse models: Ts65Dn and Dp16. Methods: A battery of behavioral tests including nestlet shredding, marble burying, nest building, and burrowing were performed to …examine apathy-like behaviors. Individual z-scores for each mouse for each test, and a composite z-score of apathy-like behavior were analyzed for all mice from these behavioral tests. Results: Analysis of individual test results and composite z-score revealed significant apathy-like behaviors in Ts65Dn mice compared to WT controls. In contrast, Dp16 mice did not exhibit significant apathy-like behaviors. Conclusions: Our study is the first to characterize apathy-like behaviors in mouse models of DS with aging and highlights the difference between Ts65Dn and Dp16 DS model mice regarding apathy-like manifestations with aging. Show more

Keywords: Alzheimer’s disease, apathy-like behavior, Down syndrome, Dp16, mouse model, Ts65Dn

DOI: 10.3233/JAD-240675

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1217-1226, 2024

Authors: Ottaviani, Silvia | Tagliafico, Luca | Muzyka, Mariya | Page, Elena | Ottaviani, Ennio | Ponzano, Marta | Signori, Alessio | Nencioni, Alessio | Monacelli, Fiammetta

Article Type: Research Article

Abstract: Background: As the population ages, the concept of frailty becomes increasingly relevant and may be considered a precursor between aging and the development of dementia in later life. Similarly, the construct of cognitive reserve (CR) is an accepted model of cognitive resilience that may account for individual differences in trajectories of brain aging, mitigating the clinical expression of dementia. Objective: We aim to estimate the role of CR and frailty in moderating the prediction of dementia in the population aged over 80 who are attending an Italian outpatient memory clinic. Methods: Comprehensive Geriatric Assessment, Clinical Frailty …Scale (CFS) to screen for frailty, and Cognitive Reserve Index questionnaire (CRIq) to evaluate CR, were used to assess patients systematically. We performed multivariate logistic regression to assess associations with dementia. Model performance and interaction between frailty and cognitive reserve were then evaluated. Results: 166 patients were consecutively enrolled (mean age was 85.7 years old, females composed 68%); 25% had a diagnosis of amnestic mild cognitive impairment, and 75% had a diagnosis of dementia. Multivariate regression analysis showed that CRIq and CFS were the main clinical assessment tools associated with the presence of dementia, even after collinearity adjustment. No significant interaction of CFS*CRIq was found. Conclusions: To our knowledge, this is the first study to investigate the association between CR, frailty, dementia, and their related interacting terms in a real-world population of very old patients. Our findings may suggest that both CR and frailty shape an individual’s resilience throughout their lifetime. This may potentially counteract the effects of brain neuropathology, in line with the hypothesis that meaningful associations exist between CR, frailty, and cognition in later life. Show more

Keywords: Alzheimer’s disease, cognitive reserve, dementia, frailty, older adults

DOI: 10.3233/JAD-231121

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1227-1235, 2024

Authors: Rosenau, Colin | Köhler, Sebastian | van Boxtel, Martin | Tange, Huibert | Deckers, Kay

Article Type: Research Article

Abstract: Background: The “LIfestyle for BRAin health” (LIBRA) index was recently updated with three new modifiable factors: hearing impairment, social contact, and sleep (LIBRA2), but has not yet been validated. Objective: Comparison of the performance of both LIBRA versions in predicting dementia risk. Methods: Longitudinal data from the English Longitudinal Study of Ageing (ELSA) and the Maastricht Aging Study (MAAS) were used. The weighted LIBRA (11/12 factors available) and LIBRA2 (14/15 factors available) scores were calculated, with higher scores representing an unhealthier lifestyle. Dementia diagnoses were based on self- or informant reported physician diagnosis, an informant-based cognitive …screening tool, registry data or test data. Cox-proportional hazards regression was used to investigate the association between LIBRA(2) scores and dementia risk. Model fit and predictive accuracy were determined using the Akaike information criterion and Harrell’s C index. Results: Over an average follow-up of 8.3 years in ELSA and 17.9 years in MAAS, 346 (4.6%) and 120 (8.5%) individuals developed dementia, respectively. In ELSA, a one-point increase in LIBRA2 was associated with an 8% (1.06–1.11) higher dementia risk (LIBRA: 13%, 1.09–1.16). In MAAS, a one-point increase in LIBRA2 was associated with a 6% (1.01–1.12) higher dementia risk (LIBRA: 8%, 0.99–1.16). In ELSA, LIBRA (Harrell’s C = 0.68) and LIBRA2 (Harrell’s C = 0.67) performed similarly. In MAAS, LIBRA2 (Harrell’s C = 0.62) performed better compared to LIBRA (Harrell’s C = 0.52) Conclusions: LIBRA2 is a better model for identifying individuals at increased dementia risk and for public health initiatives aimed at dementia risk reduction. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, healthy lifestyle, primary prevention, protective factors, risk factors, risk reduction behavior

DOI: 10.3233/JAD-240666

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1237-1248, 2024

Authors: Mattke, Soeren | Tang, Yu | Hanson, Mark | von Arnim, Christine A.F. | Frölich, Lutz | Grimmer, Timo | Onur, Oezguer A. | Perneczky, Robert | Teipel, Stefan | Thyrian, Jochen René

Article Type: Research Article

Abstract: Background: Amyloid-targeting therapies for Alzheimer’s disease (AD) might become available in Germany soon. The combination of a large pool of prevalent cases and a complex diagnostic process to determine eligibility for these treatments is likely to challenge health systems’ capacity. Objective: To analyze Germany’s healthcare system capacity to identify treatment-eligible patients in a timely and equitable manner. Methods: We modeled patients’ diagnostic journey and projects wait times due to capacity constraints for AD specialist visits and PET scans from 2024 to 2043. Model parameters were derived from published data and expert input. Results: Wait …times would be ∼50 months over the model horizon, if patients were referred to specialists based on a brief cognitive assessment in primary care. Wait times for patients with social health insurance are projected to be 1.9 times those of patients with private insurance, with peak wait times of around 76 and 40 months, respectively. Adding a blood test for the AD pathology as additional triage step would reduce wait times to below 24 months. Conclusions: In spite of having a well-resourced health system, Germany is projected to be unable to cope with the demand for biomarker-based AD diagnosis, if a disease-modifying AD treatment were introduced. As these treatments might become available by the end of 2024, decisive action, in particular dissemination of high-performing AD blood tests for triage in primary care, will be needed to prevent delays in access and potentially avoidable and inequitable disease progression. Show more

Keywords: Alzheimer’s disease, biomarker, disease-modifying treatment, health system preparedness, specialty care, diagnosis, wait times

DOI: 10.3233/JAD-240728

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1249-1259, 2024

Authors: Beckmann, Matthew N.

Article Type: Research Article

Abstract: Background: When Ronald Reagan revealed his Alzheimer’s diagnosis in 1994, it rekindled a lingering question: did dementia affect Reagan during his eight years as president? Amid countless countervailing anecdotes, Berisha et al. (2015) stepped in with an inventive systematic test. Scouring Ronald Reagan’s 46 formal press conferences for specific linguistic markers, the study discovered “significant differences in variables known to be associated with the onset of dementia” (962). Objective: Here I test whether Reagan’s unique word usage rate decline is spurious, a function of reporters’ increasing penchant for asking “follow-up” questions. Methods: Focusing on the …President’s specific responses to distinct questions, I reanalyze Reagan’s unique word usage rate while holding constant the number and type of reporter questions. Results: I find Reagan’s unique word usage rate held form throughout his eight years in the White House. Conclusions: I conclude by considering the implications for Reagan’s legacy and Alzheimer’s research. Show more

Keywords: Alzheimer’s disease, early diagnosis, natural language processing, research methodology

DOI: 10.3233/JAD-240294

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1261-1266, 2024